US4863945A - Pyrrolobenzimidazoles and pharmaceutical compositions containing them - Google Patents

Pyrrolobenzimidazoles and pharmaceutical compositions containing them Download PDF

Info

Publication number
US4863945A
US4863945A US07/131,367 US13136787A US4863945A US 4863945 A US4863945 A US 4863945A US 13136787 A US13136787 A US 13136787A US 4863945 A US4863945 A US 4863945A
Authority
US
United States
Prior art keywords
alkyl
amino
hydrogen
radical
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/131,367
Other languages
English (en)
Inventor
Walter-Gunar Friebe
Alfred Mertens
Klaus Strein
Erwin Boehm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Mannheim GmbH filed Critical Boehringer Mannheim GmbH
Assigned to BOEHRINGER MANNHEIM GMBH, SANDHOFERSTR. 116 6800 MANNHEIM 31, FEDERAL REPUBLIC OF GERMANY A WEST GERMAN CORP. reassignment BOEHRINGER MANNHEIM GMBH, SANDHOFERSTR. 116 6800 MANNHEIM 31, FEDERAL REPUBLIC OF GERMANY A WEST GERMAN CORP. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: BOEHM, ERWIN, FRIEBE, WALTER-GUNAR, MERTENS, ALFRED, STREIN, KLAUS
Application granted granted Critical
Publication of US4863945A publication Critical patent/US4863945A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is concerned with new pyrrolobenzimidazoles, processes for the preparation thereof and pharmaceutical compositions containing them.
  • the new pyrrolobenzimidazoles according to the present invention are compounds of the general formula: ##STR2## wherein R 1 is a phenyl ring of the general formula: ##STR3## in which R 5 , R 6 and R 7 , which can be the same or different, each signifies a hydrogen atom or an alkanesulphonyloxy, trifluoromethanesulphonyloxy, alkanesulphonylamino, trifluoromethanesulphonylamino, N-alkylalkanesulphonylamino, N-alkyltrifluoromethanesulphonylamino, alkyl-sulphenylmethyl, alkylsulphinylmethyl or alkyl-sulphonylmethyl radical, a carbonyl group substituted by hydroxyl, alkoxy, amino, alkylamino or dialkylamino, a sulphonyl group substituted by amino, alkylamino, dialkylamino
  • U.S. Pat. Nos. 4,666,923, 4,695,567 and 4,710,510 and Published European Patent Application No. 214 592 describe analogous compounds in which T exclusively signifies oxygen or sulphur. These compounds show a strongly inotropic action.
  • the compounds of the present invention can also be used as medicaments for the treatment of heart and circulatory diseases. In particular, they influence the thrombocyte and erythrocyte aggregation and/or increase the heart power and/or have a vasodilatory action.
  • R 1 is a phenyl ring of general formula II
  • the alkyl moiety of the substituents mentioned in the case of R 5 , R 6 and R 7 can contain 1 to 5 carbon atoms and preferably 1 to 4 carbon atoms.
  • Preferred in this sense are, for example, the methanesulphonyloxy, ethanesulphonyloxy, n-propanesulphonyloxy, isopropanesulphonyloxy, trifluoromethanesulphonyloxy, methylsulphenylmethyl, ethylsulphenylmethyl, n-propylsulphenylmethyl, methylsulphonylmethyl, ethylsulphinylmethyl, methylsulphonylmethyl, ethylsulphonylmethyl, n-propylsulphonylmethyl, methanesulphonylamino, ethanesulphonylamino, n-propanesulphonyla
  • sulphonyl groups which can be substituted by cyclic imino groups
  • the morpholino, pyrrolidino, piperidino and hexamethyleneiminosulphonyl radicals are preferred.
  • R 5 is a hydrogen atom or an alkylsulphonyloxy, trifluoromethylsulphonyloxy, alkylsulphenylmethyl, alkylsulphinylmethyl, alkylsulphonylmethyl, alkylsulphonylamino, N-alkyl-alkylsulphonylamino, trifluoromethylsulphonylamino or N-alkyltrifluoromethylsulphonylamino radical, a carbonyl group substituted by hydroxyl, alkoxy, amino, alkylamino or dialkylamino or a sulphonyl group substituted by amino, dialkylamino or morpholino, whereby each of the above-mentioned alkyl moieties can contain 1 or 2 carbon atoms, a nitro, cyano or alkylaminosulphonyl group with 1 to 4 carbon atoms, an alkylcarbonylamino, aminocarbonylamino or morpholino
  • the phenyl part can carry 1 to 3 of the mentioned substituents.
  • Preferred monosubstituted phenyl compounds include the hydroxy-, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, allyloxy-, propargyloxy-, cyanomethyloxy-, methoxycarbonylmethyloxy-, halo-, nitro-, cyano-, aminocarbonyl-, methoxycarbonyl-, amino-, C 1 -C 3 -dialkylamino-, C 1 -C 3 -alkylthio-, C 1 -C 3 -alkylsulphonyl-, C 1 -C 3 -alkylsulphonyloxy- and 1-imidazolyl-phenyls, the substituent being in the 2-, 3- or 4-position.
  • Preferred disubstituted phenyls contain, as substituents, an alkanesulphonyloxy, trifluoromethylsulphonyloxy, alkylsulphenylmethyl, alkylsulphinylmethyl, alkylsulphonylmethyl, alkylsulphonylamino, N-alkyl-alkylsulphonylamino, trifluoromethylsulphonylamino or N-alkyl-trifluoromethylsulphonylamino radical, a carbonyl group substituted by hydroxyl, alkoxy, amino, alkylamino or dialkylamino or a sulphonyl group substituted by amino, dialkylamino or morpholino, an alkylaminosulphonyl, alkylcarbonylamino, aminocarbonylamino or N-alkyl-aminocarbonylamino radical, a hydroxyl, alkyl, alkoxy, allyloxy, proparg
  • the preferred trisubstituted phenyl radical is the 3,4,5-trimethoxyphenyl radical.
  • R 1 is a heterocyclic five-membered ring with 1 to 4 heteroatoms or a heterocyclic six-membered ring with 1 to 5 heteroatoms, the heteroatoms of the above-mentioned five- and six-membered rings being the same or different and signifying nitrogen, oxygen or sulphur and possibly carrying an oxygen atom on one or more nitrogen atoms, then, in this case, there are preferred the pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, thiadiazole, oxadiazole, pyrazine, N,N'-dioxypyrazine, pyrimidine, N,N'-dioxypyrimidine, pyridazine, oxazine, thiazine, triazine, tetrazine, pyridine, N-oxypyr
  • Alkyl, alkoxy and alkylmercapto substituents in the heterocyclic five- and six-membered ring can contain 1 to 6 and preferably 1 to 4 carbon atoms, the methyl, ethyl, methoxy, ethoxy, methylthio and ethylthio radicals being preferred.
  • Halogen is to be understood to mean fluorine, chlorine or bromine and preferably chlorine.
  • the indole, indazole, benzimidazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole radicals are preferred, as well as the naphthyl radical.
  • R 1 an alkyl, alkenyl or alkynyl radical
  • X signifies a valency bond and R 1 an alkyl, alkenyl or alkynyl radical, then thereunder are to be understood straight or branched chains with up to 10 carbon atoms. Preferred in this sense are the methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, propenyl and propynyl radicals.
  • R 1 a cycloalkyl or cycloalkenyl radical
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radicals.
  • R 1 a haloalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonylaminoalkyl, alkylsulphonylaminoalkyl, alkylthio or alkylcarbonylamino radical, then the alkyl or alkoxy moieties can contain 1 to 6 carbon atoms.
  • Halogen is to be understood to be fluorine or chlorine and preferably fluorine.
  • Preferred in this sense are the trifluoromethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, carboxymethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, propoxycarbonylethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methylthio, ethylthio, propylthio, butylthio, acetylamino, propionylamino, butyloxycarbonylamino, methylsulphonylamino, formylaminopropyl, acetylaminopropyl, propionylaminopropyl and methyl
  • R 2 and R 3 are alkyl radicals then thereunder are to be understood straight or branched alkyl chains with 1 to 6 carbon atoms. Preferred in this sense are the methyl, ethyl, propyl and butyl radicals.
  • R 2 and R 3 together with the carbon atom to which they are attached, form a carbocyclic ring, then thereunder are to be understood rings with three to seven members, the cyclopropane, cyclobutane, cyclopentane and cyclohexane rings being preferred.
  • R 4 is an alkanoyl radical
  • alkanoyl radical straight-chained, branched and cyclic alkanoyl radicals with 1 to 7 carbon atoms.
  • Preferred in this sense are the formyl, acetyl and propionyl radicals.
  • X is an alkylene radical
  • alkylene radicals with 1 to 4 carbon atoms, the methylene and ethylene radicals being preferred.
  • R 1 is a phenyl radical of general formula II, wherein R 5 is a hydrogen atom, a methanesulphonyloxy, trifluoromethanesulphonyloxy, methanesulphonylamino, trifluoromethanesulphonylamino, methylthio, methylsulphinyl, methylsulphonyl, hydroxyl, methyl, methoxy, propargyloxy, trifluoromethyl or 1-imidazolyl radical, R 6 is a hydrogen or chlorine atom or a methyl, methoxy or dimethylamino radical and R 7 is a hydrogen atom or a methoxy radical or R 1 is a pyrrole, furan, thiophene, pyrazole, imidazole, isothiazole, thiazole, oxazole, triazole, tetrazole, thiadiazole, isoxazole, ox
  • the reduction mentioned in process (a) is preferably carried out in an aprotic solvent, for example, an ether, such as diethyl ether, dimethoxyethane, dioxan or tetrahydrofuran, with a complex metal hydride, for example, lithium aluminium hydride, at a temperature of from 0° to 100° C. and preferably at the boiling temperature of the solvent.
  • an aprotic solvent for example, an ether, such as diethyl ether, dimethoxyethane, dioxan or tetrahydrofuran
  • a complex metal hydride for example, lithium aluminium hydride
  • the reduction mentioned in process (b) is preferably carried out in a solvent or solvent mixture, such as water, methanol, ethanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a catalyst, such as Raney nickel, platinum or palladium/charcoal; with a metal, such as iron, tin or zinc, in the presence of an acid; with a salt, such as ferrous sulphate, stannous chloride, sodium sulphide, sodium hydrogen sulphite or sodium dithionite; or with hydrazine in the presence of Raney nickel at a temperature of from 0° to 100° C. but preferably at ambient temperature.
  • a solvent or solvent mixture such as water, methanol, ethanol, glacial acetic acid, ethyl acetate or dimethylformamide
  • the cyclisation can, if desired, be completed in that, after the reduction, heating is carried out, preferably in a solvent or solvent mixture, such as ethanol, isopropanol, glacial acetic acid, benzene, toluene, chlorobenzene, glycol, ethylene glycol dimethyl ether, sulfolan or dimethylformamide, to a temperature of from 50° to 220° C.
  • a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, toluene, chlorobenzene, glycol, ethylene glycol dimethyl ether, sulfolan or dimethylformamide
  • a condensation agent such as phosphorus oxychloride, thionyl chloride, p-toluenesulphonic acid, hydrochloric acid, sulphuric acid, phosphoric acid or polyphosphoric acid, or optionally also in the presence of a base, such as sodium hydroxide, sodium ethylate or potassium tert.-butylate.
  • a base such as sodium hydroxide, sodium ethylate or potassium tert.-butylate.
  • the cyclisation can also be carried out without the use of a solvent and/or condensation agent.
  • aldehydes aldehydes, carboxylic acids, acid halides, such as acid chlorides, carboxylic acid esters, such as methyl and ethyl esters, carboxylic acid amides and other activated carboxylic acid derivatives, as well as anhydrides and nitriles.
  • the reaction with compounds of general formula V takes place under oxidising conditions, preferably in alcoholic medium, with heating to reflux, in the presence of atmospheric oxygen and catalytic amounts of an acid, such as toluenesulphonic acid, or in the presence of atmospheric oxygen and of a catalyst, such as pyrolusite, in an acidic medium, for example in glacial acetic acid, at ambient temperature.
  • oxidising conditions preferably in alcoholic medium, with heating to reflux
  • an acid such as toluenesulphonic acid
  • a catalyst such as pyrolusite
  • the reaction with compounds of general formula V takes place in the presence of a water-removing agent, preferably in polyphosphoric acid, at a temperature of from 50° to 250° C. and preferably of from 100° to 200° C.
  • the reaction with compounds of general formula V takes place in an inert solvent, preferably in methylene chloride or pyridine.
  • an inert solvent preferably in methylene chloride or pyridine.
  • heating is subsequently carried out in a solvent or solvent mixture, such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, glycol, diethylene glycol dimethyl ether, sulfolan or dimethylformamide, to a temperature of from 50° to 250° C.
  • a condensation agent such as phosphorus oxychloride, thionyl chloride, p-toluenesulphonic acid, hydrochloric acid, sulphuric acid, phosphoric acid or polyphosphoric acid, or optionally also in the presence of a base, such as sodium hydroxide, potassium methylate or potassium tert.-butylate.
  • a base such as sodium hydroxide, potassium methylate or potassium tert.-butylate.
  • the cyclisation can also be carried out without the use of a solvent and/or condensation agent.
  • the compounds of general formulae IVa or IVb can be obtained, for example, by reacting compounds of the general formulae: ##STR8## in which T, R 2 , R 3 and R 4 have the above-given meanings, with compounds of the general formula:
  • R 1 ' and X have the above-given meanings and Z is a hydroxyl group or a residue which is easily split off.
  • the compounds of general formula V are obtained by the reduction of compounds of general formula VIIa or VIIb.
  • the reactions are preferably carried out with carboxylic acid derivatives in the presence of a water-removing agent, for example polyphosphoric acid, or of a solvent forming an azeotropic mixture with water, such as benzene or toluene.
  • a water-removing agent for example polyphosphoric acid
  • a solvent forming an azeotropic mixture with water such as benzene or toluene.
  • Reactions with activated carboxylic acid derivatives are preferably carried out in an inert solvent, for example methylene chloride or pyridine, at a temperature of from 0° C. to 250° C. but preferably at the boiling temperature of the solvent.
  • R 1 is an amino, aminoalkyl or cyclic imino group or R 1 is a heterocyclic five- or six-membered ring substituted with an amino group, such as is defined hereinbefore or R 1 is a phenyl ring of general formula II, in which one of the substituents R 5 , R 6 and R 7 is an amino, N-alkylamino or hydroxyl group, with a sulphonic acid of the general formula:
  • R 8 is an alkyl radical with 1 to 3 carbon atoms or a trifluoromethyl radical, or with a reactive derivative hereof, to give compounds of general formula I, in which the amino, aminoalkyl, cyclic imino, N-alkylamino or hydroxy radicals are sulphonated.
  • the reaction is preferably carried out in a solvent or solvent mixture, such as methylene chloride, diethyl ether, tetrahydrofuran, dioxan or benzene, optionally in the presence of an acid-binding agent, such as sodium carbonate, triethylamine or pyridine, whereby the latter two can simultaneously also be used as solvent, in the presence of an agent activating the acid or removing water, such as thionyl chloride or phosphorus pentachloride, but preferably with a reactive derivative of a compound of general formula IX, for example with an anhydride or halide thereof, such as methanesulphonic acid chloride or ethanesulphonic acid chloride, preferably at a temperature of from 0° to 100° C., for example at a temperature of from ambient temperature to 50° C.
  • a solvent or solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxan or benzene,
  • This oxidation is preferably carried out in a solvent or solvent mixture, for example in water, water/pyridine, acetone, glacial acetic acid, dilute sulphuric acid or trifluoroacetic acid, depending upon the oxidation agent used, preferably at a temperature of from -80° to 100° C.
  • the oxidation is expediently carried out with one equivalent of the oxidation agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0° to 20° C. or in acetone at 0° to 60° C.; with a per acid, such as performic acid, in glacial acetic acid or trifluoroacetic acid at 0° to 50° C. or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20° C.
  • the oxidation agent for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0° to 20° C. or in acetone at 0° to 60° C.
  • a per acid such as performic acid, in glacial acetic acid or trifluoroacetic acid at 0° to 50° C. or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20
  • the oxidation is expediently carried out with one or with two or more equivalents of the oxidation agent used, for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20° to 100° C.
  • the oxidation agent used for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20° to 100° C.
  • a per acid such as performic acid, or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at a temperature of from 0° to 60° C., with nitric acid in glacial acetic acid at 0° to 20° C., with chromic acid or potassium permanganate in glacial acetic acid, water/sulphuric acid or in acetone at 0° to 20° C.
  • a per acid such as performic acid, or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at a temperature of from 0° to 60° C.
  • nitric acid in glacial acetic acid at 0° to 20° C.
  • chromic acid or potassium permanganate in glacial acetic acid, water/sulphuric acid or in acetone at 0° to 20° C.
  • the reaction is preferably carried out in a solvent or solvent mixture, such as methylene chloride, ethanol, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an agent activating the acid or of a water-removing agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N',N-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or of an agent activating the amino group, for example phosphorus trichloride, and optionally in the presence of an inorganic base
  • water formed during the reaction can be removed by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a drying agent, such as anhydrous magnesium sulphate or a molecular sieve.
  • reaction is carried out especially advantageously in a corresponding halide, for example a carboxylic acid or sulphonic acid chloride, and a corresponding amine, which can simultaneously serve as a solvent, and at a temperature of from 0° to 50° C.
  • a corresponding halide for example a carboxylic acid or sulphonic acid chloride
  • a corresponding amine which can simultaneously serve as a solvent
  • This alcoholysis and/or hydrolysis is carried out either in the presence of an acid, such as hydrochloric acid, sulphuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in an appropriate solvent, such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan, at a temperature of from -10° to 120° C., for example at a temperature from ambient temperature to the boiling temperature of the reaction mixture.
  • an acid such as hydrochloric acid, sulphuric acid, phosphoric acid or trichloroacetic acid
  • a base such as sodium hydroxide or potassium hydroxide
  • an appropriate solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan
  • the reactions are preferably carried out in a solvent, such as acetone, ether, benzene, toluene or dimethylformamide, at a temperature of from -30° C. to +100° C. and preferably at ambient temperature, in the presence of a base, such as potassium carbonate or sodium hydride, and of an alkylation agent, such as an alkyl halide or alkyl sulphate.
  • a solvent such as acetone, ether, benzene, toluene or dimethylformamide
  • a base such as potassium carbonate or sodium hydride
  • an alkylation agent such as an alkyl halide or alkyl sulphate.
  • the hydrogenation is preferably carried out in a solvent, such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, preferably with hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium/charcoal.
  • the oxidation is preferably carried out with one or more equivalents of the oxidation agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20° to 100° C. or in acetone at 0° to 60° C., with a per acid, such as performic acid or m-chloroperbenzoic acid, in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at a temperature of from 0° to 60° C.
  • the compounds obtained of general formula I can subsequently, if desired, be converted into their physiologically acceptable acid-addition salts with inorganic or organic acids.
  • acids there can be used, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulphonic acid.
  • the compounds of general formula I are mixed in known manner with appropriate pharmaceutical carrier substances, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvant materials, suspended or dissolved in water or an oil, for example olive oil.
  • the new compounds according to the present invention of general formula I and the salts thereof can be administered enterally or parenterally in liquid or solid form.
  • injection medium water is preferably used which contains the additives usual in the case of injection solutions, such as stabilising agents, solubilising agents or buffers.
  • Such additives include, for example, tartrate and citrate buffers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • Sold carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
  • Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
  • the compounds according to the present invention are usually administered in amounts of from 10 to 500 mg. per day, referred to 75 kg. body weight. It is preferred to administer 2 to 3 times per day 1 or 2 tablets with an active material content of 5 to 200 mg. The tablets can also be retarded in which case it is only necessary to give 1 or 2 tablets with 10 to 500 mg. of active material once per day.
  • the active material can also be given by injection 1 to 8 times per day or by continuous infusion, amounts of 5 to 200 mg./day thereby normally being sufficient.
  • Preferred compounds according to the present invention are, apart from those mentioned in the Examples, also the following and the tautomers thereof:
  • Example 2b A mixture of 60 g. polyphosphoric acid, 1.6 ml. trifluoroacetic acid, 18 g. phosphorus pentoxide and 4.0 g. (18 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline (Example 2b) is stirred for 7 hours at 150°-160° C. The reaction mixture is allowed to cool to 90° C., poured on to ice, left to stand overnight and filtered to give 1.7 g. (31%) of the title compound; m.p. 290°-291° C.
  • the product is purified over a silica gel column (elution agent 1,1,1-trichloroethane/methanolic ammonia 15:1 v/v). The appropriate fractions are evaporated in a vacuum, the oil obtained is taken up in hot ethanol, diethyl ether is added thereto until turbidity commences and then left to crystallise. There are obtained 2.8 L g. of the title compound; m.p. 286°-288° C.
  • the average arterial pressure, the heart rate and dp/dt max (derivative of the pressure in the left ventricle with respect to time--a measure of the force of the myocardial contraction)--were determined as hemodynamic parameter.
  • Normotensive Sprague Dawley rats were anaesthetized with Inaktin i.p.
  • To Facilitate spontaneous breathing, the animals were provided with a tracheal tube.
  • a Miller Mikro-Tip was placed in the left ventricle to record the left ventricular pressure (LVP) and dp/dt max was determined with the help of a computer.
  • the vena jugularis served as i.v. access.
  • the arterial pressure was measured by means of a catheter and a pressure transducer by way of the arteria femoralis.
  • the EKG and the heart rate were derived by way of subcutaneous puncture electrodes.
  • the doses were fractionated and applied cumulative from 0.01 to 30 mg/kg at 10-minute intervals.
  • the ED +1 .5 mHg/sec of the substances investigated is given in Table 1. It is understood to be the particular effective dose, which increases the control value by 1.5 mHg/sec.
  • Table 2 shows the behavior of the average arterial pressure and of the heart rate. The starting values (control) were compared with the values after a dose of 1 mg/kg.
  • the erythrocyte aggregation was determined with the mini-erythrocyte aggregometer of the Myrenne Co., Roetgen, West Germany, [1]. As a measure of the aggregation, this instrument displays a dimensionless index, which increases with the increasing state of aggregation.
  • the blood which was adjusted to a hematocrit of 45%, was incubated with the control solution or with the substance solutions. Subsequently, the erythrocyte aggregation was measured. Each substance was analyzed at a concentration of 10 -6 M and 10 -5 M. The difference in the aggregation indices between the initial value of the control solution and the values with the substance solution was calculated.
  • Venoruton a mixture of different o-(beta-hydroxyethyl)rutosides, brings about merely a decrease in the erythrocyte aggregation index of 0.38. Even at a concentration of 1.7 ⁇ 10 -3 M the reduction in the erythrocyte aggregation is only 3.9 ⁇ 0.9. Venoruton is intended to inhibit the tendency of erythrocytes to aggregate [2]. In comparison with Venoruton, the substances of this invention clearly reduce the erythrocyte aggregation more.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US07/131,367 1986-12-11 1987-12-10 Pyrrolobenzimidazoles and pharmaceutical compositions containing them Expired - Fee Related US4863945A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3642315 1986-12-11
DE19863642315 DE3642315A1 (de) 1986-12-11 1986-12-11 Neue pyrrolobenzimidazole, verfahren zu ihrer herstellung sowie arzneimittel

Publications (1)

Publication Number Publication Date
US4863945A true US4863945A (en) 1989-09-05

Family

ID=6315954

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/131,367 Expired - Fee Related US4863945A (en) 1986-12-11 1987-12-10 Pyrrolobenzimidazoles and pharmaceutical compositions containing them

Country Status (13)

Country Link
US (1) US4863945A (pt)
EP (1) EP0271040A3 (pt)
JP (1) JPS63162692A (pt)
KR (1) KR880007536A (pt)
AU (1) AU8245087A (pt)
DD (1) DD267047A5 (pt)
DE (1) DE3642315A1 (pt)
DK (1) DK650187A (pt)
FI (1) FI875438A7 (pt)
HU (1) HU200339B (pt)
IL (1) IL84589A0 (pt)
PT (1) PT86331B (pt)
ZA (1) ZA879166B (pt)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026271A1 (en) * 1993-05-14 1994-11-24 Medical College Of Pennsylvania Treatment of cryptococcus neoformans infection
US20050261313A1 (en) * 2001-01-12 2005-11-24 Amgen Inc. Substituted alkylamine derivatives and methods of use
US20060069145A1 (en) * 2004-09-24 2006-03-30 Georges Guy Tricycles, their manufacture and use as pharmaceutical agents
US20060142247A1 (en) * 2004-12-17 2006-06-29 Guy Georges Tricyclic heterocycles
US20060235065A1 (en) * 2005-04-14 2006-10-19 Guy Georges Aminopyrazole derivatives
US20060235013A1 (en) * 2005-04-14 2006-10-19 Guy Georges Tricyclic azole derivatives
US20090143375A1 (en) * 2005-12-15 2009-06-04 F. Hoffmann-La Roche Ag Tricyclic Lactam Derivatives, Their Manufacture and Use as Pharmaceutical Agents
US20090291968A1 (en) * 2006-03-23 2009-11-26 Guy Georges Substituted indazole derivatives, their manufacture and use as pharmaceutical agents
US20100190777A1 (en) * 2007-07-17 2010-07-29 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8642624B2 (en) 2001-01-12 2014-02-04 Amgen Inc. Substituted alkylamine derivatives and methods of use
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206240A (en) * 1989-12-08 1993-04-27 Merck & Co., Inc. Nitrogen-containing spirocycles
DE4027592A1 (de) * 1990-08-31 1992-03-05 Beiersdorf Ag Neue pyrrolobenzimidazole, imidazobenzoxazinone und imidazochinolone, verfahren zu ihrer herstellung und ihre verwendung sowie die verbindungen enthaltende zubereitungen
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
EP1598353A1 (en) * 2004-05-17 2005-11-23 Boehringer Ingelheim International GmbH Pyrrolobenzimidazolones and their use as antiproliferative agents

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0214592A2 (de) * 1985-09-05 1987-03-18 Roche Diagnostics GmbH Neue Pyrrolo-Benzimidazole, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
US4666923A (en) * 1984-05-12 1987-05-19 Boehringer Mannheim Gmbh Pyrrolobenzimidazoles for treating heart or circulatory diseases
US4695567A (en) * 1985-01-18 1987-09-22 Boehringer Mannheim Gmbh Pyrrolobenzimidazoles, pharmaceutical compositions containing them and method of using them to treat certain heart and circulatory diseases
US4710510A (en) * 1984-12-14 1987-12-01 Boehringer Mannheim Gmbh Pyrrolobenzimidazoles, pharmaceutical compositions containing them, and use of them to treat certain heart and circulatory diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4666923A (en) * 1984-05-12 1987-05-19 Boehringer Mannheim Gmbh Pyrrolobenzimidazoles for treating heart or circulatory diseases
US4710510A (en) * 1984-12-14 1987-12-01 Boehringer Mannheim Gmbh Pyrrolobenzimidazoles, pharmaceutical compositions containing them, and use of them to treat certain heart and circulatory diseases
US4695567A (en) * 1985-01-18 1987-09-22 Boehringer Mannheim Gmbh Pyrrolobenzimidazoles, pharmaceutical compositions containing them and method of using them to treat certain heart and circulatory diseases
EP0214592A2 (de) * 1985-09-05 1987-03-18 Roche Diagnostics GmbH Neue Pyrrolo-Benzimidazole, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5434163A (en) * 1993-05-14 1995-07-18 The Medical College Of Pennsylvania Treatment of Cryptococcus neoformans infection
WO1994026271A1 (en) * 1993-05-14 1994-11-24 Medical College Of Pennsylvania Treatment of cryptococcus neoformans infection
US20050261313A1 (en) * 2001-01-12 2005-11-24 Amgen Inc. Substituted alkylamine derivatives and methods of use
US8642624B2 (en) 2001-01-12 2014-02-04 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7687643B2 (en) 2001-01-12 2010-03-30 Amgen Inc. Process for preparing 3,3-dimethylindolines
US7285569B2 (en) 2004-09-24 2007-10-23 Hoff Hoffmann-La Roche Inc. Tricycles, their manufacture and use as pharmaceutical agents
US20060069145A1 (en) * 2004-09-24 2006-03-30 Georges Guy Tricycles, their manufacture and use as pharmaceutical agents
US20060142247A1 (en) * 2004-12-17 2006-06-29 Guy Georges Tricyclic heterocycles
US20060235013A1 (en) * 2005-04-14 2006-10-19 Guy Georges Tricyclic azole derivatives
US20060235065A1 (en) * 2005-04-14 2006-10-19 Guy Georges Aminopyrazole derivatives
WO2006108489A1 (en) * 2005-04-14 2006-10-19 F. Hoffmann-La Roche Ag Aminopyrazole derivatives, their manufacture and use as pharmaceutical agents
US7462639B2 (en) 2005-04-14 2008-12-09 Hoffmann-La Roche Inc. Aminopyrazole derivatives
US20090143375A1 (en) * 2005-12-15 2009-06-04 F. Hoffmann-La Roche Ag Tricyclic Lactam Derivatives, Their Manufacture and Use as Pharmaceutical Agents
US20090291968A1 (en) * 2006-03-23 2009-11-26 Guy Georges Substituted indazole derivatives, their manufacture and use as pharmaceutical agents
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US20100190777A1 (en) * 2007-07-17 2010-07-29 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US12076322B2 (en) 2011-02-07 2024-09-03 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds

Also Published As

Publication number Publication date
PT86331A (de) 1988-01-01
EP0271040A2 (de) 1988-06-15
HU200339B (en) 1990-05-28
DD267047A5 (de) 1989-04-19
AU8245087A (en) 1988-06-16
KR880007536A (ko) 1988-08-27
DK650187D0 (da) 1987-12-10
PT86331B (pt) 1990-11-07
FI875438A7 (fi) 1988-06-12
IL84589A0 (en) 1988-04-29
DE3642315A1 (de) 1988-06-23
ZA879166B (en) 1988-06-14
JPS63162692A (ja) 1988-07-06
HUT47278A (en) 1989-02-28
FI875438A0 (fi) 1987-12-10
DK650187A (da) 1988-06-12
EP0271040A3 (de) 1989-11-02

Similar Documents

Publication Publication Date Title
US4863945A (en) Pyrrolobenzimidazoles and pharmaceutical compositions containing them
US4954498A (en) Tricyclic benzimidazole compounds, pharmaceutical compositions and methods of use
US4666923A (en) Pyrrolobenzimidazoles for treating heart or circulatory diseases
US4882342A (en) 5-alkylbenzimidazoles, method of use and pharmaceutical compositions
US5414088A (en) 2-bicyclobenzimidazoles, processes for their preparation and medicaments containing these compounds
US4666908A (en) 5-Substituted pyrazolo[4,3-d]pyrimidine-7-ones and methods of use
US4851406A (en) Heterocyclic-substituted indoles and pharmaceutical compositions containing them
AU719392B2 (en) Nitrogen-containing heterocyclic compounds
US4695567A (en) Pyrrolobenzimidazoles, pharmaceutical compositions containing them and method of using them to treat certain heart and circulatory diseases
US5373019A (en) Pharmaceutical lactam compositions for inhibition of erythrocyte and thrombocyte aggregation
US4810801A (en) Pyrrolobenzimidazoles, pharmaceutical compositions containing them, and use of them to treat certain heart and circulatory diseases
US4874756A (en) Benzodipyrroles, processes for the preparation thereof and pharmaceutical compositions containing them
US5019587A (en) Bicyclic carboxamides, compositions containing same and use thereof
NZ201294A (en) Imidazoquinoxaline derivatives
US4835280A (en) Indoline compounds for synthesis of pharmaceutically active pyrrolobenzimidazoles
US4730003A (en) Tricyclic compounds for treating heart and circulatory diseases
US4925845A (en) 2 heteroaryl 3,3 dialkyl-5-(3 oxo-2,3,4,5 tetrahydro-6 pyridazinyl)-3H-indoles
US5137890A (en) 4-phenyl tetrahydropyrido(4,3-d)pyrimidines
US5212186A (en) Cardioactive pyrrolobenzimidazoles
US4831032A (en) Cardiotonic benzimidazoles
CA1141382A (en) 2-(1-piperazinyl)-cycloheptimidazole derivatives
US5053508A (en) Fused heterotricyclic imides with psychotropic activity and intermedrates thereof
JPS62135475A (ja) ２−置換−ｅ−融合−〔１，２，４〕トリアゾロ−〔１，５−Ｃ〕ピリミジン

Legal Events

Date Code Title Description
AS Assignment

Owner name: BOEHRINGER MANNHEIM GMBH, SANDHOFERSTR. 116 6800 M

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:FRIEBE, WALTER-GUNAR;MERTENS, ALFRED;STREIN, KLAUS;AND OTHERS;REEL/FRAME:004816/0822

Effective date: 19871204

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 20010905

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362